Nicotine, Neurotrophins and Depression

尼古丁、神经营养素和抑郁症

• 批准号: 7163147
• 负责人: YOUSEF TIZABI
• 金额: $ 15.77万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7163147
• 关键词: amines; antidepressants; behavior test; depression; dopamine receptor; gas chromatography mass spectrometry; high performance liquid chromatography; laboratory rat; microdialysis; neurotransmitter receptor; nicotine; nicotinic receptors; norepinephrine; pharmacokinetics; psychopharmacology; receptor binding; receptor sensitivity; serotonin receptor; statistics /biometry; stereotaxic techniques

Because of high incidence of cigarette smoking among depressed individuals, it has been postulated that smoking may reflect an attempt at self-medication with nicotine by these individuals. However, other studies suggest that smoking may precede depression. Recent findings by us and others depict a complex involvement of nicotine and nicotinic system in mood regulation. Thus, nicotine acutely or chronically may act as an antidepressant in Fliners Sensitive Line (FSL) rats, a strain with inherent depressive-like behavior. However, in WKY rats, another putative animal model of depression, depending on the administered regimen, nicotine may act as an antidepressant or a "depressogenic" agent by exacerbating the depressive characteristics of these rats. Hence, the questions of when and how nicotine may act as an antidepressant or a depressogenic or what central mechanisms may mediate its effects remain unanswered. Recent findings strongly suggest that the brain-derived neurotrophic factor (BDNF) may be a common denominator in the mechanism of action of all antidepressants. Hence, the major aim of this proposal is to elucidate the interactions between nicotine, BDNF and its high affinity receptor Trk-B in relation to depression. Specifically, the following hypotheses will be evaluated: 1. Antidepressant effects of nicotine will be associated with an increase in BDNF and Trk-B densities in hippocampal and other areas implicated in mood regulation, and the "depressogenic" effects of nicotine will be associated with an opposite effect on these parameters. 2. The antidepressant effects of nicotine will be associated with an anti-apoptotic activity and depressogenic effects of nicotine will be associated with a pro-apoptotic activity. 3. Clinically effective antidepressants that are also effective in this model will increase BDNF, Trk-B and antiapoptotic activities. 4. Clinically effective antidepressants that are not effective in this model will not affect BDNF or apoptotic activities. 5. Serum BDNF levels will be decreased in depressive states and effective antidepressants will elevate serum BDNF levels. Behavioral analyses will include Porsolt forced swim test and general locomotor activity. BDNF and TrkB containing neurons will be quantified by immunocytochemical and state of the art stereological techniques. TUNEL staining and stereological quantification will be applied to determine the extent of apoptosis. Enzyme-linked immunosorbent assay (ELISA) will be used to quantify the serum levels of BDNF. The results of these studies can: 1. provide answers to the seemingly contradictory effects of nicotine on mood, 2. indicate a common determinant for antidepressant effectiveness, and 3. suggest a possible peripheral marker for the depressive state and/or efficacy of antidepressant treatments. The findings may also facilitate the development and evaluation of novel antidepressants and/or compounds useful in smoking cessation.

由于沮丧的人在吸烟中吸烟的发病率很高，因此已经假设 吸烟可能反映了这些人与尼古丁进行自我治疗的尝试。但是，其他研究 表明吸烟可能在抑郁症之前。我们和其他人的最新发现描绘了一个复杂的 尼古丁和烟碱系统参与情绪调节。因此，尼古丁急性或长期可能 在Fliners敏感线（FSL）大鼠中充当抗抑郁药，这是一种固有的抑郁样行为的菌株。 但是，在WKY大鼠中，另一个假定的抑郁症模型，具体取决于管理 尼古丁方案，尼古丁可以通过加剧抑郁症来充当抗抑郁药或“抑郁剂”药物 这些大鼠的特征。因此，何时以及如何充当抗抑郁药的问题 或降压生成或中心机制可能介导其效果的哪些中心作用仍未得到解答。最近的 发现强烈表明，脑衍生的神经营养因子（BDNF）可能是一个共同点 在所有抗抑郁药的作用机理中。因此，该提议的主要目的是阐明 尼古丁，BDNF及其高亲和力受体TRK-B之间的相互作用与抑郁症有关。具体来说， 将评估以下假设：1。尼古丁的抗抑郁作用将与 海马以及与情绪调节有关的其他领域的BDNF和TRK-B密度的增加，以及 尼古丁的“降压”作用将与这些参数产生相反的作用。 2 尼古丁的抗抑郁作用将与抗凋亡活性和降压作用有关 尼古丁将与促凋亡活性有关。 3。临床上有效的抗抑郁药也是 在此模型中有效将增加BDNF，TRK-B和抗凋亡活性。 4。临床有效 在此模型中无效的抗抑郁药不会影响BDNF或凋亡活动。 5。血清 BDNF水平将在抑郁状态下降低，有效抗抑郁药将升高血清BDNF 水平。行为分析将包括Porsolt强制游泳测试和一般的运动活动。 bdnf和 含有TRKB神经元的TRKB将通过免疫细胞化学和艺术的状态定位 技术。 TUNEL染色和立体定量将用于确定 凋亡。酶联免疫吸附测定法（ELISA）将用于量化BDNF的血清水平。 这些研究的结果可以：1。为尼古丁对看似矛盾的影响提供答案 情绪2。表示抗抑郁效果的共同决定因素，3。 抗抑郁治疗的抑郁状态和/或功效的外围标记。发现可能 还促进新型抗抑郁药和/或化合物的开发和评估有用 停止。